Chromatin-based mechanisms control the cell-specific and hypoxia-regulated expression of endothelial nitric oxide synthase.
Published: 2006
Language: eng
Number of pages: 300
ISBN-13: 9780494219201
Description: Endothelial nitric oxide synthase (eNOS) is highly restricted in expression to vascular endothelial cells of medium- to large-sized arteries. We hypothesize that chromatin-based mechanisms are operative in eNOS cell-specific expression. Here we identify a differentially methylated region that is localized to eNOS proximal promoter DNA. This region is densely methylated in non-endothelial cell types such as vascular smooth muscle cells, but is devoid of methylation in primary vascular endothelial cell types. We also demonstrate that the eNOS promoter is enriched in acetylated histone H3 and H4 and di- and tri-methylation of histone H3 (lysine 4) in endothelial cells, but not nonendothelial cells. An endothelial-specific histone acetylation code is present at the eNOS promoter that consists of acetylation of lysine 9 of histone H3 and lysine 12 of histone H4. DNA methylation and post-translational histone modifications are functionally important in regulating eNOS cell-specificity as modulating these pathways results in expression of the eNOS gene in normally non-expressing cell types. Histone modifications are also implicated in the down-regulation of eNOS in disease states, as we demonstrate that hypoxia transcriptionally down-regulates eNOS in endothelial cells by modulating the eNOS histone code. Repression of eNOS is mediated by histone eviction of proximal promoter nucleosomes(s) and their associated post-translational modifications. While histories are replaced following long-term exposure to hypoxic conditions, these histories are hypoacetylated. Reoxygenation results in the re-acetylation of the eNOS promoter and alleviates transcriptional repression. We therefore present evidence that chromatin-based mechanisms play a role in the cell-specific and regulated expression of eNOS.
Notes: Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0151.

Thesis (Ph.D.)--University of Toronto, 2006.

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